Dear Editor of Journal of Heart and Cardiology,
I hope you will find the enclosed manuscript, “Inverted Takotsubo Cardiomyopathy due to use to BetaAgonist Therapy” enlightening and worthy of sharing with your readers in the Cardiology Research
Journal.
The manuscript describes a patient we cared for in our teaching hospital. My faculty mentor, (Dr. Ali and
Dr. White), our Pubmed researcher helper (Dr. Siddique) and I (Yaser Jbara, MD) have shared in
reviewing this case as well as preparing this manuscript. Thus we meet the criteria for authorship and
will sign statements attesting authorship and releasing the copyright should our manuscript be accepted
for publication. The above doctors and I have no potential conflicts of interest to disclose. All of our
tables and figures are original.
We are submitting our work as a case report. Our patient gave verbal consent for his de-identified
medical information to be published as a medical case report.
If you have further questions feel free to contact me; I am the lead author as well as the corresponding
author.
Contact information:
1) Omair Ali, MD
Wright State University, Boonshoft School of Medicine
Department of Cardiology Fellowship
Weber CHE Building, Second Floor
128 East Apple Street
Dayton, OH 45409-2902
Omairy2j@gmail.com
2) Yaser Jbara, MD
Wright State University, Boonshoft School of Medicine
Department of Internal Medicine
Weber CHE Building, Second Floor
128 East Apple Street
Dayton, OH 45409-2902
Jbarayaser@yahoo.com
3) Bryan White MD, FACC
Wright State University, Boonshoft School of Medicine
Department of Cardiology Fellowship
Weber CHE Building, Second Floor
128 East Apple Street
Dayton, OH 45409-2902
bryan.white.2@us.af.mil
4) Faisal Siddique MD
Khyber Medical College, University Of Peshawar
Department of Medicine
Road No. 2, University of, Peshawar 25120, Pakistan
Phone: 937-776-5822
FAX: (937) 208-2621
Sincerely,
Yaser Jbara, MD
Internal Medicine Residency Program, Wright State University, Boonshoft School of Medicine
Inverted Takotsubo Cardiomyopathy due to use to Beta-Agonist
Therapy
Omair M. Ali MD, Yaser Jbara MD, Faisal Siddique MD, Bryan White
MD, FACC
Introduction
Takotsubo cardiomyopathy is a transient acute left ventricular dysfunction characterized by left
ventricular apical akinesis and ballooning without obstructive coronary disease. It is described
predominantly in post-menopausal women in the setting of acute emotional or physical stress. Recent
reports have described isolated transient basal akinesis (inverted takotsubo cardiomyopathy) in mostly
female patients with acute neurologic disorders or pheochromocytoma. We describe a rare case of a
patient with inverted takotsubo cardiomyopathy in the setting of acute exacerbation of chronic obstructive
pulmonary disease.
Case Presentation
A 54 female with a history of very severe chronic obstructive pulmonary disease (COPD) presented to our
ER for progressive dyspnea, worsening cough and sputum production. Her ROS was negative for angina,
palpitations, presyncope, or fevers and chills. Her vital signs were notable for being afebrile, a heart rate
of 94 beats per minute, blood pressure of 163/75 mm Hg, respiratory rate of 28 per minute with an
oxygen saturation of 100 percent on 10 Liter delivered via face mask. Examination had revealed severely
diminished breath sounds and diffused expiratory wheezing.

Complete blood count and basic metabolic panel were otherwise normal.

Her arterial blood gas showed a pH of 7.33, partial pressure of carbon dioxide of 52.6 mm Hg and
partial pressure of oxygen 170 mm Hg on an FIO2 of 10 liters.

D-Dimer was 205 ng/ml (the reference range <500 ng/ml) which excluded pulmonary embolism.


BNP was 278.
Cardiac enzymes for CK 193, CK-MB 5.1, RI 2.8% and TnI 0.21μg/l
myocardial infarction of 0.07 μ g/l).

Admission chest radiograph revealed hyper expanded lung fields. An electrocardiogram obtained
revealed sinus tachycardia, without acute ST changes.

A left heart catheterization (Figures A, B) revealed non-obstructive coronary arteries. A
ventriculogram (Figures C, D) obtained during the procedure revealed apical hyperkinesis and
basal hypokinesis.

A dedicated echocardiogram (Figures E,F) revealed moderate left ventricular dysfunction (EF of
45 percent). There was severe basilar akinesis of the inferior walls with relative apical
hyperkinesia.

A contrast enhanced echocardiogram revealed similar findings. (Figures G, H).
Differential Diagnosis
(cutoff value for


Her differential at the time of admission were limited to NSTEMI, thought to be secondary to
epicardial artery plaque rupture. As she had concomitant COPD exacerbation, she was given
ipratropium bromide, albuterol sulfate inhalers and oral corticosteroids.
She was discharged home in a stable condition. A follow-up echocardiogram (Figure I, J) 23
days later revealed a normal left ventricular size, wall thickness and systolic function (EF of 60
percent). Previous regional wall abnormalities had resolved.
Discussion
TCM is a non-ischemic cardiomyopathy characterized by transient dysfunction that conventionally
involves the apical left ventricle. There is compensatory hyperkinesia of the basal walls, with resultant
apical ballooning. Due to this characteristic appearance it was described as "tako tsubo" (or octopus trap)
in Japan in 1990 by Dote et al. 1 Since then, it has also been recognized as Stress-induced
cardiomyopathy, transient apical ballooning syndrome, ampulla cardiomyopathy, Gebrochenes-Herz
Syndrome and “broken heart syndrome”.
The latter term comes in to popularity given a strong association with severe emotional stress that occurs
most commonly in post-menopausal females. According to a study by Sharkley et al, these events may be
financial hardships, loss of a loved one, family arguments, divorce and situations with high anxiety such
as social phobias. 2 Additional physical triggers have also been described. While the original case reports
were from Japan, takotsubo cardiomyopathy has been noted more recently in the Western hemisphere. It
is likely that the syndrome went previously undiagnosed before it was described in detail in the Japanese
literature. The absolute prevalence in the general population still remains unclear.
Gianni et al presented a study looking at patients presenting with suspected acute coronary syndrome,
many of which were determined to have Takotsubo cardiomyopathy. The reported prevalence in this
study was 1.7% to 2.2% 3 The above study, was one of many to describe the typical presentation of this
clinical entity, which often mirrors that of acute myocardial infarction. 4 This includes chest pain and
shortness of breath, although dyspnea as the only clinical manifestation of the disease has also been
reported.5, 6 EKG changes may range from ST-segment depression or elevation that often evolves to
diffuse T-wave inversions. Further cardiac biomarkers may also be elevated. 4, 7, 8 Abrupt left ventricular
dysfunction may lead to complications such as acute decompensated heart failure or acute pulmonary
edema, arrhythmias and even cardiogenic shock.
Although there is no universal consensus for the diagnostic criteria of Takotsubo cardiomyopathy, the
Mayo Clinic has proposed the following 4 obligatory criteria 9 1) Transient hypokinesis, akinesis, or
dyskinesis of the left ventricular mid segments with or without apical involvement, with the regional wall
motion abnormalities extending beyond a single epicardial vascular distribution. 2) Absence of
obstructive coronary disease or angiographic evidence of acute plaque rupture 3) New EKG abnormalities
or elevation in cardiac troponin, and 4) The absence of pheochromocytoma and myocarditis.
Shimizu et al. 10 was the first to classify this cardiomyopathy into different types based on ballooning
patterns. They describe a) The conventional type for apical akinesia and basal hyperkinesia, b) The midventricular type for mid-ventricular ballooning accompanied by basal and apical hyperkinesia c) The
localized type for any other segmental left ventricular ballooning with clinical characteristics of
takotsubo-like left ventricular dysfunction, and d) The inverted takotsubo type (reverse) for basal akinesia
and apical hyperkinesia
Kurowski et al found 14 of 35 cases (40%) of Takotsubo Cardiomyopathy to be of the inverted type. 11
Like the conventional takotsubo, inverted takotsubo cardiomyopathy has also been reported in association
with pheochromocytoma. 12,13, It had recently also been reported with physical stressors such as acute
cerebrovascular accident, paraganglioma 15,16 and acute pancreatitis 19. There is an account of occurrence
following shoulder surgery. 20 It has been reported with amphetamine 14 and adderall
(dextroamphetamine) use 17. There is a single report in association with post partal state. 18
This is the first case to our knowledge associated with COPD exacerbation. The diagnosis of concomitant
Takotsubo Cardiomyopathy becomes challenging given a) dyspnea may occur in either COPD
exacerbation and/or Takotsubo Cardiomyopathy b) clinical examination alone cannot illicit underlying
Cardiomyopathy c) EKG changes in both disease may be similar and non pathogomonic d) Troponin
elevation may occur secondary to hypoxemia related exacerbation or acute Takotsubo Cardiomyopathy.
Our diagnosis came by echocardiographic evidence of basal hypokinesis and apical hyperkinesis, after
left ventriculography revealed abnormal basilar ventricular function. Moreover angiography revealed
patent coronaries.
We theorize that a combination of subendocardial ischemia from hypoxemia in addition to the beta
agonists given during management may have differentially affected beta receptors leading to the inverted
pattern that was observed. The prognosis for TCM is generally favourable as is evident by the dramatic
improvement in ventricular function in nearly all patients. Our patient had a complete resolution of all of
her symptoms and of her cardiomyopathy.
Learning Points

TCM is a non-ischemic cardiomyopathy characterized by transient dysfunction that
conventionally involves the apical left ventricle. There is compensatory hyperkinesia of the basal
walls, with resultant apical ballooning.

Inverted Takotsubo Cardiomyopathy is a rare variant characterized by the converse, that is, basal
hypokinesis and apical hyperkinesis.

High catecholamine states should be ruled out in this setting. We theorize that a combination of
subendocardial ischemia from hypoxemia in addition to the beta agonists given during
management may have differentially affected beta receptors leading to the inverted pattern that
was observed.

Inverted Takotsubo Cardiomyopathy has a generally favourable prognosis characterized by
complete resolution of the cardiomyopathy.
Fig.A
Fig B
Figure A and B: Angiogram excluding luminal irregularities in the left (A) and right (B) coronary
circulation.
Fig. C
Fig D
Figures C and D. End-systolic (C) and end-diastolic (D) left ventriculography showing moderate
segmental left ventricular dysfunction, with akinesia of the basal and midventricular segments and
apical hypercontractility.
Fig. E
Fig. F
End-systolic (E) and end-diastolic (F) frames of two chamber view on initial echocardiography taken
following hospital admission, showing severe left ventricular systolic dysfunction with akinesia of the
left ventricular base and mid-portion, and hypercontractility of the apex.
Fig G
Fig H
Fig G and H. Contrast enhanced Echocardiography at diastole (G) and systole (H) showing basal
hypokinesis and apical hyperkinesis.
Fig I
Fig J
Fig I and J. A follow up echocardiography at the end of systole (I) and diastole (J) taken 23 days later
showing nearly normalized cardiac function without regional wall motion abnormalities.
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